In retinal degenerations, such as retinitis pigmentosa (RP), rod-specific mutations cause rod photoreceptors to die by apoptosis, as well as the non-cell autonomous degeneration of cone photoreceptors, pigment epithelium and choroid that lead to debilitating blindness. The molecular events that lead to photoreceptor apoptosis and the non-cell autonomous effects are not known. In this proposal, the following specific aims examine the mechanisms responsible for autonomous and non-Cell autonomous degeneration from genetic mutations causing retinal degeneration in rodent models of RP, with particular attention to the role of cell death factors and survival factors: (1) to determine the cell death mechanisms by comparing the expression of apoptosis-signaling molecules in retinas from rodent models of RP and age-matched normal retinas using Western blot analysis, (2) to determine the importance of death-inducing factors, survival-promoting factors, and Muller glia and microglia in non-cell autonomous photoreceptor degeneration using dissociated mutant and normal rodent retinal cells, in both monolayer and reaggregate cocultures, and (3) to analyze in detail the onset and progression of both primary and secondary effects of the mutation, both in vivo and in vitro, using an inducible transgenic model of RP. The proposed studies could elucidate the cell death mechanisms in RP, providing new points for intervention in the treatment of retinal degenerations.